Synthesis and Cytotoxicity Studies of New Cryptophycin Analogues

Liu, Wen Lu; Zhang, Jian Cun; Jiang, Fa Qin; Fu, Lei

doi:10.1002/ardp.200900067

Cited by 11 publications

(12 citation statements)

References 12 publications

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“…52 An improved method to access unit C precursors from b-azidopivalic acid (31) avoiding alkylating agents was introduced Scheme 2 Unit A precursor 14 synthesis using an enantioselective crotylboration. 42 recently. 32,34 31 can be synthesized in one step from cheap commercially available b-chloropivalic acid (30) in very high yields.…”

Section: Unit Cmentioning

confidence: 99%

Recent approaches for the synthesis of modified cryptophycins

2013

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Cryptophycins are a family of antimitotic depsipeptides with very high cytotoxicity even against multi-drug resistant (MDR) cancer cells. The first representative was isolated from cyanobacteria Nostoc sp. in 1990. Their bioactivity is based on their interaction with the protein tubulin. Cryptophycins were found to induce apoptosis due to inhibition of the microtubule dynamics. Consequently, cryptophycin analogues are considered as potential antitumour agents. Retrosynthetically, cryptophycins can be subdivided into four building blocks, namely units A-D, to be assembled in the total synthesis. Since the discovery of this compound class, numerous synthetic analogues have been designed for structure-activity relationship (SAR) studies. This review gives a critical overview on cryptophycins, while the main focus lies on the synthetic challenges of recently published cryptophycins, together with emerging concepts on cryptophycin bioconjugation and prodrug design.

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Section: Unit Cmentioning

confidence: 99%

Recent approaches for the synthesis of modified cryptophycins

2013

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“…Two cryptophycin analogs with an elongated unit B fragment have been reported (Figure ) . The Arndt–Eistert reaction served as the key step in the synthesis of the corresponding homologated unit B building block, a β ‐amino acid.…”

Section: Cryptophycin Analogs and Sar Studiesmentioning

confidence: 99%

“…Cryptophycin analogs with an elongated unit B building block (IC 50 values in n m ) . Cell lines: K562, multidrug‐resistant human leukemia; LoVo, human colon carcinoma.…”

Section: Cryptophycin Analogs and Sar Studiesmentioning

confidence: 99%

Cryptophycins: cytotoxic cyclodepsipeptides with potential for tumor targeting

Weiß

Figueras

Borbély

et al. 2017

Journal of Peptide Science

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Cryptophycins are a class of 16-membered highly cytotoxic macrocyclic depsipeptides isolated from cyanobacteria. The biological activity is based on their ability to interact with tubulin. They interfere with microtubule dynamics and prevent microtubules from forming correct mitotic spindles, which causes cell-cycle arrest and apoptosis. Their strong antiproliferative activities with 100-fold to 1000-fold potency compared with those of paclitaxel and vinblastine have been observed. Cryptophycins are highly promising drug candidates, as their biological activity is not negatively affected by P-glycoprotein, a drug efflux system commonly found in multidrug-resistant cancer cell lines and solid tumors. Cryptophycin-52 had been investigated in phase II clinical trials but failed because of its high neurotoxicity. Recently, cryptophycin conjugates with peptides and antibodies have been developed for targeted delivery in tumor therapy.

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“…However, due to the novel mechanism of action, other cryptophycin analogues are being investigated. Preliminary results show cytotoxic activity of two lactam analogues of cryptophycin 1 in the MDR human leukemia cell line K562 …”

Section: Drugs Able To Evade P‐glycoproteinmentioning

confidence: 99%

“…Preliminary results show cytotoxic activity of two lactam analogues of cryptophycin 1 in the MDR human leukemia cell line K562. 219 In addition, a hybrid structure in which one portion is characteristic of a cryptophycin and the other an epothilone named cryptothilone has been synthesized. The mechanism of action has not yet been clarified, but it has been shown that this compound has no affinity for either cryptophycin or the taxol/epothilone binding site on tubulin.…”

Section: Cryptophycinsmentioning

confidence: 99%

Overcoming tumor multidrug resistance using drugs able to evade P‐glycoprotein or to exploit its expression

Nobili

Landini

Mazzei

et al. 2011

Medicinal Research Reviews

149

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Multidrug resistance (MDR) is a major obstacle to the effective treatment of cancer. Cellular overproduction of P-glycoprotein (P-gp), which acts as an efflux pump for various anticancer drugs (e.g. anthracyclines, Vinca alkaloids, taxanes, epipodophyllotoxins, and some of the newer antitumor drugs) is one of the more relevant mechanisms underlying MDR. P-gp belongs to the superfamily of ATP-binding cassette transporters and is encoded by the ABCB1 gene. Its overexpression in cancer cells has become a therapeutic target for circumventing MDR. As an alternative to the classical pharmacological strategy of the coadministration of pump inhibitors and cytotoxic substrates of P-gp and to other approaches applied in experimental tumor models (e.g. P-gp-targeting antibodies, ABCB1 gene silencing strategies, and transcriptional modulators) and in the clinical setting (e.g. incapsulation of P-gp substrate anticancer drugs into liposomes or nanoparticles), a more intriguing strategy for circumventing MDR is represented by the development of new anticancer drugs which are not substrates of P-gp (e.g. epothilones, second- and third-generation taxanes and other microtubule modulators, topoisomerase inhibitors). Some of these drugs have already been tested in clinical trials and, in most of cases, show relevant activity in patients previously treated with anticancer agents which are substrates of P-gp. Of these drugs, ixabepilone, an epothilone, was approved in the United States for the treatment of breast cancer patients pretreated with an anthracycline and a taxane. Another innovative approach is the use of molecules whose activity takes advantage of the overexpression of P-gp. The possibility of overcoming MDR using the latter two approaches is reviewed herein.

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Synthesis and Cytotoxicity Studies of New Cryptophycin Analogues

Cited by 11 publications

References 12 publications

Recent approaches for the synthesis of modified cryptophycins

Recent approaches for the synthesis of modified cryptophycins

Cryptophycins: cytotoxic cyclodepsipeptides with potential for tumor targeting

Overcoming tumor multidrug resistance using drugs able to evade P‐glycoprotein or to exploit its expression

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